In women, the risk of developing hypertension and/or cardiovascular diseases increases after entering the menopause, where ovulation stops (Aflalo-Calderon B. HRT, women, and heart disease: what we need to know about prevention, Medscape Cardiology 6(2), 2002). It is thought that the treatment of post-menopausal women with estrogens would antagonise the risk of hypertension and/or cardiovascular diseases, such as hypertension. However, the risk of developing hypertension and/or cardiovascular diseases by the current forms of hormone replacement therapy has not yet been verified (Nelson et al. Post-menopausal hormone replacement therapy. J Am Medical Ass, Aug. 21, 2002, vol 288, no 7, pp 872-891).
Hypertension has for many years been thought to be the pre-dominant factor in the development of cardiovascular diseases, but it has now been questioned to what extent anti-hypertensive agents such as ACE inhibitors prevents the development of cardiovascular diseases in women. ACE inhibitors act through maintaining electrolyte homeostasis via the renin-angiotensin-aldosterone system (RAAS) such that plasma levels of the mineralocorticoid hormone, aldosterone, are reduced due to the inhibiting of the activation of mineralocorticoid receptors in the epithelia of the kidney, colon and sweat glands, whereby aldosterone promotes the retention of sodium and the excretion of potassium.
However, recently it has been shown that mineralocorticoid receptors are also present in the cardiovascular system, such as in the heart and blood vessels, as well as in the brain (Delayani JA: Mineralocorticoid receptor antagonists; the evolution of utility and pharmacology. Kidney INt, 2000 Apr 57(4) 1408-1411). Moreover, animal and human studies point to the fact that aldosterone plays a role in the pathogenesis of cardiovascular and renal diseases independent of the well-known mechanism involving activation of the angiotensin to angiotensin II (Stier et al, aldosterone as a mediator in cardiovascular injury. Cardiol Rev 2002, mar-Apr 10(2), 97-102). Thus, it is to be expected that aldosterone via its activation of the mineralocorticoid receptors in the heart, blood vessels or brain will mediate several pathophysiological actions like for example stroke, cardiac fibrosis, ventricular hypertrophy, myocardial necrosis, heart failure (congestive heart failure), sudden cardiac death and/or myocardial infarction.
Eplerenone is a steroidal drug with aldosterone receptor blocker activity. Eplerenone is reported as being effective in the treatment of aldosterone-mediated diseases such as cardiovascular diseases (Martin and Krum; Eplerenone. Current opinion in investigational drugs, 2001, 2(4), 521-525). Eplerenone has a selective binding to the mineralocorticoid receptor in that other steroidal receptors are not affected, such as the estrogenic and progestational receptors. Eplerenone has been shown to provide cardioprotection in both women and men (Hamedii and Chadow: The promise of selective aldosterone receptor antagonist for the treatment of hypertension and congestive heart failure. Curr Hypertens Rep, 2000, Aug 2(4), 378-383, Delayani et al: Eplerenone; a selective aldosterone receptor antagonist (SARA), cardiovascular Drug Rev 2001 FAII, 19(3) 185-200).
Another drug substance is Spironolactone (17-hydroxy-7-alpha-mercapto-3-oxo-17-alpha-pregn-4-ene-21-carboxylic acid gamma-lactone acetate), which has been shown to decrease the morbidity and mortality among patients with severe heart failure who were already receiving ACE inhibitor therapy. Thus, an additive effect was observed (Pitt et al; the effect of Spironolactone on morbidity and mortality in patients with severe heart failure. New Engl. J Med, vol 341, no 10, pp 709717, 1999).
Aldosterone antagonists have been used in the treatment of aldosterone mediated pathogenic effects such as hypertension and/or cardiovascular diseases in a subject that has salt sensitivity or an elevated dietary sodium intake or both by administering one or more aldosterone antagonists such as Spironolactone (WO 01/95892).
WO 02/09759 relates to the treatment of inflammation-related cardiovascular disorders such as aetherosclerosis in a subject by administering an aldosterone antagonist and a cyclooxygenase-2 inhibitor. The aldosterone antagonist being a spirolactone-type compound (Spironolactone) and an epoxy-steroidal aldosterone antagonist.
WO 01/34132 relates to the treatment, inhibiting or preventing pathogenic change resulting from vascular injury in a human subject by administering an aldosterone antagonist.
WO 95/15166 relates to the treatment with an aldosterone antagonist such as Spironolactone and epoxymexrenone for inhibiting myocardial fibrosis in that the dosage used may not disrupt a patient's normal electrolyte and water-retention balance.
Drospirenone (DRSP), a 17α-spirolactone is an analogue to Spironolactone. Drospirenone has unlike other known progestins biochemical and pharmacological profiles similar to endogenous progesterone, especially with regard to the anti-mineralocorticoid activity in the epithelia of the kidney, colon and sweat glands and the anti-androgenic activity (Krattenmacher R; Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 2000, July, 62(1), 29-38; Norman P, Drospirenone. Drugs of the future 2000, 25(12, 1247-1256). Therefore, Drospirenone is thought to mediate the natural anti-aldosterone and vasoactive properties of endogenous progesterone in women. It is known that Drospirenone binds to mineralocorticoid receptors in competition with aldosterone so as to provide a strong anti-mineralocorticoid activity. Drospirenone is about 8 times as potent as Spironolactone (Pollow et al; dihydrospirorenone, a novel synthetic progestagen, characterisation of binding to different receptor proteins. Contraception, 1992, 46, 561-574).
Drospirenone is known from the patent DE 19633685 and the patent application WO 98067838, both relate to a process for producing Drospirenone, 6β,7β;15β;16β-dimethylene-3-oxo-17α-preg-4-ene-21,17-carbolactone.
Plasma aldosterone levels may be affected by administering Drospirenone: In a study implying administration of Drospirenone alone or Drospirenone in combination with ethinylestradiol demonstrated that the plasma aldosterone levels increased in both groups of therapy. (Oelkers et al: Effect of an oral contraceptive containing Drospirenone in the renin-angiotensin-aldosterone system in healthy female volunteers, Gynecol endocrinol 2000, 14, 204-213).
Furthermore, it has been shown that Drospirenone in combination with 17β-estradiol further reduces hypertension in postmenopausal women that suffer from hypertension and is in therapy with an ACE inhibitor, Enalapril (Preston et al, Additive effect of drospirenonell/17β-estradiol in hypertensive postmenopausal women receiving Enalapril (Am J Hypertension, 2002, 15 (816-822).
Drospirenone is further known from its use in contraception (WO 01/15701) and for managing HRT in post-menopausal women (WO 01/52857).